SIDE EFFECTS

Approximately 3600 patients with osteoarthritis were treated with VIOXX (rofecoxib) ; approximately 1400 patients received VIOXX (rofecoxib) for 6 months or longer and approximately 800 patients for one year or longer. The following table of adverse experiences lists all adverse events, regardless of causality, occurring in at least 2% of patients receiving VIOXX (rofecoxib) in nine controlled studies of 6-week to 6-month duration conducted in patients with OA at the therapeutically recommended doses (12.5 and 25 mg), which included a placebo and/or positive control group.

The following serious adverse events have been reported rarely (estimated <0.1%) in patients taking VIOXX (rofecoxib) , regardless of causality. Cases reported only in the post-marketing experience are indicated in italics.

In 1-year controlled clinical trials and in extension studies for up to 86 weeks (approximately 800 patients treated with VIOXX (rofecoxib) for one year or longer), the adverse experience profile was qualitatively similar to that observed in studies of shorter duration.

Approximately 1,100 patients were treated with VIOXX (rofecoxib) in the Phase III rheumatoid arthritis efficacy studies. These studies included extensions of up to 1 year. The adverse experience profile was generally similar to that reported in the osteoarthritis studies. In studies of at least three months, the incidence of hypertension in RA patients receiving the 25 mg once daily dose of VIOXX (rofecoxib) was 10.0% and the incidence of hypertension in patients receiving naproxen 500 mg twice daily was 4.7%.

Approximately one thousand patients were treated with VIOXX (rofecoxib) in analgesia studies. All patients in post-dental surgery pain studies received only a single dose of study medication. Patients in primary dysmenorrhea studies may have taken up to 3 daily doses of VIOXX (rofecoxib) , and those in the post-orthopedic surgery pain study were prescribed 5 daily doses of VIOXX (rofecoxib) .

The adverse experience profile in the analgesia studies was generally similar to those reported in the osteoarthritis studies. The following additional adverse experience, which occurred at an incidence of at least 2% of patients treated with VIOXX (rofecoxib) , was observed in the post-dental pain surgery studies: post-dental extraction alveolitis (dry socket).

Approximately 750 patients were treated with a single dose of VIOXX (rofecoxib) 25 mg or 50 mg in two single-attack migraine studies. Approximately 460 patients in the 3-month extension phase of one study treated up to 8 (average 3) migraine attacks per month. In single attack studies, the following adverse events were more frequent in the VIOXX (rofecoxib) treatment groups (25 mg and 50 mg) compared to the placebo group, and occurred at an incidence of at least 2% of patients treated: dizziness, nausea, somnolence and dyspepsia. In the 3-month extension phase of one study, the following adverse events occurred at an incidence of at least 2% of patients treated in the VIOXX (rofecoxib) treatment groups (25 mg and 50 mg): dizziness, dry mouth, nausea, and vomiting.

In a 12-week study, 209 JRA patients, ≥ 2 years to ≤ 17 years of age, were treated with rofecoxib; 109 and 100 patients were treated with lower-dose rofecoxib and higher-dose rofecoxib, respectively. In a 52-week open-label extension, 160 JRA patients, ≥ 2 years to ≤ 17 years of age, were treated with higher-dose rofecoxib for up to 15 months. No new adverse experiences were identified other than a single case of pseudoporphyria (a photo-induced blistering reaction), an adverse event that has been seen in patients with JRA treated with non-selective NSAIDs. In this 12-week study, the most common adverse experiences (at 0.6 mg/kg dose) were upper abdominal pain, nasopharyngitis, diarrhea, upper respiratory tract infection, abdominal pain, headache and rhinitis. Rash was also reported.

*adverse experience that resulted in death, permanent or substantial disability, hospitalization, congenital anomaly, or cancer, was immediately life threatening, was due to an overdose, or was thought by the investigator to require intervention to prevent one of the above outcomes

DRUG INTERACTIONS

ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors. In patients with mild to moderate hypertension, administration of 25 mg daily of VIOXX (rofecoxib) with the ACE inhibitor benazepril, 10 to 40 mg for 4 weeks, was associated with an average increase in mean arterial pressure of about 3 mm Hg compared to ACE inhibitor alone. This interaction should be given consideration in patients taking VIOXX (rofecoxib) concomitantly with ACE inhibitors.

Concomitant administration of low-dose aspirin with VIOXX (rofecoxib) may result in an increased rate of GI ulceration or other complications, compared to use of VIOXX (rofecoxib) alone. In a 12-week endoscopy study conducted in OA patients there was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking low-dose (81 mg) enteric coated aspirin plus VIOXX (rofecoxib) 25 mg daily, as compared to those taking ibuprofen 2400 mg daily alone. Patients taking low-dose aspirin plus ibuprofen were not studied. (See CLINICAL STUDIES, Special Studies, Upper Endoscopy in Patients with Osteoarthritis and Rheumatoid Arthritis.)

At steady state, VIOXX (rofecoxib) 50 mg once daily had no effect on the anti-platelet activity of low-dose (81 mg once daily) aspirin, as assessed by ex vivoplatelet aggregation and serumTXB2 generation in clotting blood. Because of its lack of platelet effects, VIOXX (rofecoxib) is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, in patients taking VIOXX (rofecoxib) , antiplatelet therapies should not be discontinued and should be considered in patients with an indication for cardiovascular prophylaxis. (See CLINICAL STUDIES, Special Studies, Platelets and PRECAUTIONS, Cardiovascular Effects.) Prospective, long-term studies on concomitant administration of VIOXX (rofecoxib) and aspirin have not been conducted.

Cimetidine

Co-administration with high doses of cimetidine [800 mg twice daily] increased the Cmax of rofecoxib by 21%, the AUC0-120hr by 23% and the t1/2 by 15%. These small changes are not clinically significant and no dose adjustment is necessary.

Digoxin

Rofecoxib 75 mg once daily for 11 days does not alter the plasma concentration profile or renal elimination of digoxin after a single 0.5 mg oral dose.

Furosemide

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandinsynthesis.

Ketoconazole

Ketoconazole 400 mg daily did not have any clinically important effect on the pharmacokinetics of rofecoxib.

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In post-marketing experience there have been reports of increases in plasma lithium levels. Thus, when VIOXX (rofecoxib) and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

VIOXX (rofecoxib) 12.5, 25, and 50 mg, each dose administered once daily for 7 days, had no effect

on the plasma concentration of methotrexate as measured by AUC0-24hr in patients receiving single weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. At higher than recommended doses, VIOXX (rofecoxib) 75 mg administered once daily for 10 days increased plasma concentrations by 23% as measured by AUC0-24hr in patients receiving methotrexate 7.5 to 15 mg/week for rheumatoid arthritis. At 24 hours postdose, a similar proportion of patients treated with methotrexate alone (94%) and subsequently treated with methotrexate co-administered with 75 mg of rofecoxib (88%) had methotrexate plasma concentrations below the measurable limit (5 ng/mL). Standard monitoring of methotrexate-related toxicity should be continued if VIOXX (rofecoxib) and methotrexate are administered concomitantly.

Oral Contraceptives

Rofecoxib did not have any clinically important effect on the pharmacokinetics of ethinyl estradiol and norethindrone.

Prednisone/prednisolone

Rofecoxib did not have any clinically important effect on the pharmacokinetics of prednisolone or prednisone.

Rifampin

Co-administration of VIOXX (rofecoxib) with rifampin 600 mg daily, a potent inducer of hepatic metabolism, produced an approximate 50% decrease in rofecoxib plasma concentrations. Therefore, a starting daily dose of 25 mg of VIOXX (rofecoxib) should be considered for the treatment of osteoarthritis when VIOXX (rofecoxib) is co-administered with potent inducers of hepatic metabolism.

Theophylline

VIOXX (rofecoxib) 12.5, 25, and 50 mg administered once daily for 7 days increased plasma theophylline concentrations (AUC(0-∞)) by 38 to 60% in healthy subjects administered a single 300-mg dose of theophylline. Adequate monitoring of theophylline plasma concentrations should be considered when therapy with VIOXX (rofecoxib) is initiated or changed in patients receiving theophylline. These data suggest that rofecoxib may produce a modest inhibition of cytochrome P450 (CYP) 1A2. Therefore, there is a potential for an interaction with other drugs that are metabolized by CYP 1A2 (e.g., amitriptyline, tacrine, and zileuton).

Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing VIOXX (rofecoxib) therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. In single and multiple dose studies in healthy subjects receiving both warfarin and rofecoxib, prothrombin time (measured as INR) was increased by approximately 8% to 11%. In post-marketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving VIOXX (rofecoxib) concurrently with warfarin.

Last reviewed on RxList: 12/28/2004
This monograph has been modified to include the generic and brand name in many instances.